Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9" (BCAR-D-19-00296R2)

Amand F Schmidt, Michael V Holmes, Richard W Morris, Yoav Ben-Shlomo, et al.

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Abstract

Background
We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.

Methods
Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration

Results
The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95%CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95%CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95%CI 0.57; 1.22) for the GS, compared to 0.85 (95%CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95%CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable.

Conclusions
Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown although precision was moderate.
Original languageEnglish
Article number240
Number of pages10
JournalBMC Cardiovascular Disorders
Volume19
DOIs
Publication statusPublished - 29 Oct 2019

Keywords

  • Genetic association studies
  • Mendelian randomisation
  • LDL-cholesterol
  • phenome-wide association scan

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